Heme metabolism dental2012

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Biochemistry
Second Year

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Heme metabolism dental2012

  1. 1. HEME METABOLISM 1
  2. 2. Outline of this lecture topic……. a. Porphyrins & structure of Heme b. Synthesis of Heme c. Regulation of Heme synthesis d. Porphyrias e. Degradation of Heme f. Jaundice g. Genetic disorders related to Bilirubin metabolism 2
  3. 3. Porphyrins Porphyrins are cyclic compounds composed by 4 pyrrole rings held together by methenyl ( =CH-) bridges. Metal ions can bind with nitrogen atoms of pyrrole ring to form a complex Heme is a iron containing porphyrins 3
  4. 4. Structure of Heme Heme contains 1. A porphyrin molecule namely protoporphyrin IX which consist of - four pyrrole rings - with pyrrole rings 4 methyl (-CH3), 2 vinyl (-CH=CH2) and 2 propionyl (CH2-CH2-COO) groups are attached 2. Ferrous form of iron (Fe2+) are present in center. 4
  5. 5. Biosynthesis of Heme - Biosynthesis of heme primarily occurs in - Liver - Erythrocytes producing cells of bone marrow (erythroid cells) - Stages of Biosynthesis of heme 1. Formation of δ-aminolevulinic acid 2. Synthesis of porphobilinogen 3. Formation of porphyrin ring 4. Conversion of uroporphyrinogen III to protoporphyrin IX 5. Synthesis of heme from protoporphyrin IX 5
  6. 6. Outline of Heme synthesis 6 Mitochondrion Cytoplasm Succinyl-CoA Glycine δ-amino levulinic acid porphobilinogen hydroxymethylbilane uroporphyrinogen III coproporphyrinogen IIIProtoporphyrinogen III Heme Protoporphyrin IX Hydroxymethylbilane synthase (PBG deaminase) Uroporphyrinogen III synthase Uroporphirinogen III decarboxylase Coproporphyrigen III oxidase Protoporphyrinogen III oxidase Ferrochelatase δ ALA-synthase ALA-dehydratase +
  7. 7. Regulation of Heme synthesis Two different mechanisms exist in regulation of heme biosynthesis in the Liver and the erythroid cells 1. Regulation in liver δ-ALA The first committed step in heme biosynthesis catalyzed by ALA synthase is regulatory. 7
  8. 8. 2. Regulation in Erythroid cells Heme synthesis in Erythroid cells are controlled by a. Uroporphyrinogen III synthase b. Ferrochelatase - Heme or its oxidized product hemin (Fe+3) controls this enzyme activity by three mechanisms a. Feedback inhibition b. Repression of ALA synthase c. Inhibition of transport of ALA synthase from the cytosol to mitochondria(the site of action) 8
  9. 9. PORPHYRIAS -A group of rare metabolic disorders caused by deficiencies of enzymes of the heme biosynthetic pathway. -Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations -The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme -However, congenital erythropoietic porphyria is an exception ( Autosomal recessive) 9
  10. 10. TYPES of PORPHYRIAS 1. ALA-dehydratase deficiency porphyria 2. Acute intermittent porphyria 3. Congenital erythropoietic porphyria 4. Prophyria cutanea tarda 5. Herediatary coproporphyria 6. Variegate porphyria 7. Erythropoietic protoporphyria 10
  11. 11. PORPHYRIAS GLYCINE + SuccinylCoA -aminolevulinic acid(ALA) Porphobilinogen(PBG) hydroxymethylbilane uroporphyrinogen III coprophyrinogene III Protoporphyrinogene IX protoporphyrin IX Heme ALA synthase ALA dehydratase Hydroxymethylbilane Synthase(PBG deaminase) Uroporphyrinogen III cosynthase Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferrochelatase ALA-dehydratase deficiency porphyria Acute intermittent porphyria Uroporphyrinogen decarboxylase Congenital erythropoietic porphyria Prophyria cutanea tarda Herediatary coproporphyria Variegate porphyria Erythropoietic protoporphyria DEFICIENCY of ENZYME PORPHYRIAs 11
  12. 12. Acute Intermittent Porphyria -Autosomal dominant mode of inheritance -Caused by a deficiency in Hydroxymethylbilane synthase (PBG deaminase)which is involved in the conversion of porphobilinogen (PBG) to uroporphyrinogen III -PBG and δ-ALA accumulate in the plasma and the urine and urine get darkened on exposure to air due to the conversion of PBG to porphobilin and porphyrin. -Characteristics features are - Usually expressed after puberty in humans - Symptoms include abdominal pain, vomiting, cardiovascular abnormality and neuropsychiatric disturbance - patients are not photosensitive 12
  13. 13. Congenital erythropoietic porphyria - Due to deficiency of Uroporphyrinogen III cosynthase. - Characteristic features are a. Rare congenital disorder caused by autosomal recessive mode of inheritance. b. Patients excrete uroporphyrinogen I and coproporphyrinogen I which oxidized respectively to uroporphyrine I and corpoporphyrin I. c. The patients are photosensitive due to accumulation of abnormal porphyrin 13
  14. 14. Porphyria cutanea tarda -Most common porphyria -Autosomal dominant mode of inheritance -Disease is caused by a deficiency in uroporphyrinogen decarboxylase, which is involved in the conversion of uroporphyrinogen III to coproporphyrinogen III -Characteristic features are 1. Increased excretion of uroporphyrin I and III and rarely porphobilinogen 2. Patients are photosensitive (cutaneous photosensitivity) 3. Liver exhibits fluorescence due to high concentration of accumulated porphyrins 14
  15. 15. DEGRADATION OF HEME 15
  16. 16. FATE OF RED BLOOD CELLS -Life span of RBCs are about 120 days -At the end of this period, RBCs are phagocytosed and/or lysed -Normally, lysis occurs extravascularly by the macrophages of the reticuloendothelial system in liver and spleen. -Lysis can also occur intravascularly (in blood stream) -About 80% of heme subjected for degradation comes from RBC. 20% comes from immature RBC, myoglobin and cytochromes. 16
  17. 17. Phagocytosis & Lysis Hemoglobin Globin Amino acids Amino acid pool Heme Bilirubin Fe2+ Excreted 17
  18. 18. Outline of Degradation of hemoglobin 18
  19. 19. DEGRADATION OF HEME TO BILIRUBIN (Unconjugated) “unconjugated” bilirubin -About 80%% of heme is derived from RBCs -In normal adults this results in a daily load of 250-300 mg of bilirubin Hydrophobic – transported by albumin to the liver for further metabolism prior to its excretion 19
  20. 20. NORMAL BILIRUBIN METABOLISM In liver unconjugated bilirubin is conjugated with glucoronic acid catalyzed by UDP glucuronyl tranferase “Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to urobilinogen (colorless) by bacteria in the gut Oxidized to stercobilin which is colored and excreted in feces Some stercobilin may be re- adsorbed by the gut and re- excreted by either the liver or kidney 20
  21. 21. HYPERBILIRUBINEMIA -Recognized clinically as jaundice -Jaundice is classified into three major types a. Prehepatic or hemolytic jaundice b. Hepatic jaundice c. Posthepatic or obstructive jaundice Normal value of serum bilirubin a. Total Bilirubin 0.2-1 mg/dl b. Conjugated 0.1-0.4 mg/dl c. Unconjugated 0.1-0.6 mg/dl -Hyperbilirubinemia is defined as increased plasma concentrations of bilirubin occurs when there is an imbalance between its production and excretion 21
  22. 22. Prehepatic (hemolytic) jaundice -Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis -Excess RBC lysis is commonly the result of a. Rh- or ABO incompatibility b. structurally abnormal RBCs (Sickle cell disease) c. Malaria -High plasma concentrations of unconjugated bilirubin (normal concentration 0.1-0.6 mg/dL) 22
  23. 23. Intrahepatic jaundice -Impaired uptake, conjugation, or secretion of bilirubin by liver -Reflects a generalized liver (hepatocyte) dysfunction or damage ie a. Viral Hepatitis b. Cirrhosis of Liver c. Poisons and toxins which damage the liver cells - Increased serum level of conjugated and unconjugated bilirubin is usually accompanied by other abnormalities in biochemical markers of liver function 23
  24. 24. Posthepatic jaundice 1.Caused by an obstruction of the biliary tree. 2. Characterized by - Increased concentration of conjugated bilirubin in serum. - Serum Alkaline phosphatase is elevated. - Pale colored stools (due to absence of faecal stercobilin - dark urine ( due to increased conjugated bilirubin) 24
  25. 25. Neonatal Jaundice (Physiological jaundice of newborn) -Common, particularly in premature infants -It occurs due to a. immaturity of the enzymes involved in bilirubin conjugation ( UDP glucuronyl Transferase) b. limitation of availability of the substrate UDP- glucoronic acid. - Unconjugated bilirubin is highly elevated in serum. High levels of unconjugated bilirubin are toxic to the new- born – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus. -If bilirubin levels are judged to be too high, then phototherapy with blue light is used to convert it to a water soluble, non-toxic isomer called Lumirubin which can easily excreted through urine 25
  26. 26. Genetic Disorders of Bilirubin Metabolism 26

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